Cell cycle inhibitors in normal and tumor stem cells

Cheng, Tao

doi:10.1038/sj.onc.1207945

Cited by 91 publications

(85 citation statements)

References 137 publications

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“…Runx1 belongs to a family of cancer genes (8), and our data so far suggested that Runx1 downregulates the mRNA expression of the skin tumor suppressor gene Cdkn1a (58) in HFSCs and stimulates epithelial and HFSC proliferation. Moreover, SC overproliferation is thought to increase the risk of cancer development (12,35). Therefore, we next asked whether the Runx1 cKO would impair papilloma and squamous cell carcinoma (SCC) formation in response to skin DMBA/TPA carcinogenic treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cdkn1a modulates proliferation of tissue stem cells, such as blood and brain cells, during normal homeostasis and in response to stress, senescence, and aging by blocking cells in the G 0 /G 1 and G 1 /S phases of the cell cycle (12). Moreover, Cdkn1a (p21) KO mouse newborn keratinocytes showed increased proliferation in vitro, accompanied by an enhanced short-term engraftment ability in vivo (58).…”

Section: Discussionmentioning

confidence: 99%

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Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

Hoi

Lee

et al. 2010

Molecular and Cellular Biology

107

135

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Runx1/AML1 is a transcription factor implicated in tissue stem cell regulation and belongs to the small Runx family of cancer genes. In the hair follicle (HF), Runx1 epithelial deletion in morphogenesis impairs normal adult hair homeostasis (cycle) and blocks adult hair follicle stem cells (HFSCs) in quiescence. Here, we show that these effects are overcome later in adulthood. By deleting Runx1 after the end of morphogenesis, we demonstrate its direct role in promoting anagen onset and HFSC proliferation. Runx1 deletion resulted in cyclin-dependent kinase inhibitor Cdkn1a (p21) upregulation. Interfering with Runx1 function in cultured HFSCs impaired their proliferation and normal G 0 /G1 and G 1 /S cell cycle progression. The proliferation defect could be rescued by Runx1 readdition or by p21 deletion. Chemically induced skin tumorigenesis in mice turned on broad Runx1 expression in regions of the skin epithelium, papillomas, and squamous cell carcinomas. In addition, it revealed reduced rates of tumor formation in the absence of Runx1 that were accompanied by decreased epithelial levels of phospho-Stat3. Runx1 protein expression was similar in normal human and mouse hair cycles. We propose that Runx1 may act as a skin oncogene by directly promoting proliferation of the epithelial cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

Hoi

Lee

et al. 2010

Molecular and Cellular Biology

107

135

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“…Cisplatin is an important drug in the treatment of ovarian cancer, but one of its major limitations is that the initial response is always followed by the acquisition of drug resistance (Song et al, 2007). In light of the view that cancer-initiating cells have a crucial role in the development of drug-resistance (Zhang et al, 2008) Cell cycle control is one of the important aspects in CSC biology and deregulated cell cycle control is one of the fundamentally intrinsic steps leading to CSC-derived tumorigenesis (Cheng, 2004). To determine whether differences in proliferation, differentiation and chemoresistance observed between CD24 þ and CD24 À cells isolated from ovarian cancer were due to differences in the cell cycle distribution, the cell cycle status of each population were analyzed by flow cytometry.…”

Section: Growth Properties Of Purified Cd24mentioning

confidence: 99%

CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells

et al. 2010

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Cancer stem cells (CSCs) have been identified in solid tumors and cancer cell lines. In this study, we isolated a series of cancer cell clones, which were heterogeneous in growth rate, cell cycle distribution and expression profile of genes and proteins, from ovarian tumor specimens of a patient and identified a sub-population enriched for ovarian CSCs defined by CD24 phenotype. Experiments in vitro demonstrated CD24þ sub-population possessed stem celllike characteristics of remaining quiescence and more chemoresistant compared with CD24À fraction, as well as a specific capacity for self-renewal and differentiation. In addition, injection of 5 Â 10 3 CD24 þ cells was able to form tumor xenografts in nude mice, whereas equal number of CD24 À cells remained nontumorigenic. We also found that CD24 þ cells expressed higher mRNA levels of some 'stemness' genes, including Nestin, b-catenin, Bmi-1, Oct4, Oct3/4, Notch1 and Notch4 which were involved in modulating many functions of stem cells, and lower E-cadherin mRNA level than CD24 À cells. Altogether, these observations suggest human ovarian tumor cells are organized as a hierarchy and CD24 demarcates an ovarian cancer-initiating cell population. These findings will have important clinical applications for developing effective therapeutic strategies to treat ovarian cancer.

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“…A similar function is identified for p16, p21, p27, and p57. More important, cell cycle-related proteins regulate cell cycle via the modulation of the cyclinsCDKs-CDKIs network (as reviewed by Tao) [43]. Besides, several other new cell cycle-related factors have been reported: butyric acid [44], ''ataxia telangiectasia mutated'' (Atm) gene [45], HTm4 gene [46], RUNX family [47], Jak2 with the V617F point mutation [48], nucleophosmin [49], RhoAN19 GTPase [50], neurokinin-A [51], Hedgehog (Hh) proteins [52].…”

Section: Cell Cycle Regulationmentioning

confidence: 99%

Expansion of hematopoietic stem/progenitor cells

Deng

Duan

2008

American J Hematol

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Hematopoietic stem/progenitor cells (HSPCs) transplantation is hampered by the low number of stem cells per sample. To tackle this obstacle, several protocols for expansion of HSPCs in vitro are currently in development, such as the use of cytokine cocktails, coculture with mesenchymal stem cells as feeder cells, and cell culture in bioreactors. With the progress in the understanding of the molecular and cellular mechanisms regulating HSPCs maintenance and expansion, more recent approaches have involved transcription regulation, cell cycle regulation, telomerase regulation, and chromatin-modifying agents. The potential clinical application and safety issues relevant to the expanded HSPCs are also discussed in this review. Am. J. Hematol. 83:922-926, 2008. V

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Cell cycle inhibitors in normal and tumor stem cells

Cited by 91 publications

References 137 publications

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

Runx1 Directly Promotes Proliferation of Hair Follicle Stem Cells and Epithelial Tumor Formation in Mouse Skin

CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells

Expansion of hematopoietic stem/progenitor cells

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